The objective of this proposal is to investigate the role of host genetic variation and gene-environment interactions in determining susceptibility to complex occupational and environmental diseases. This proposal is well aligned with NTP goals and NIEHS Genes and Environment Initiative aiming to identify the genetic and environmental basis of common diseases. NIOSH is in a unique position to significantly advance research in gene-environment interactions through availability of large populations with well-documented phenotypic and exposure information. The studies conducted as part of this project have been focused on common occupational/environmental exposures/diseases with growing global occupational and public health concerns. For example, irritant contact dermatitis is a major health problem affecting both general and occupational populations and is caused by exposure to industrial and pharmaceutical chemicals as well as plant products. It accounts for 15% - 20% of all reported occupational diseases. This project investigates the genetic basis of irritant contact dermatitis in healthcare workers and allergic contact dermatitis in subjects with metal allergies. Asthma induced by low molecular weight agents and chronic beryllium disease are also among the most common occupational/environmental disorders. These diseases represent an ideal model to study gene-environment interaction as detailed genetic and exposure information is available. Understanding these interactions is an integral step towards the goal of NIOSH and NIEHS to improve occupational and public health since some environmental and occupational factors that influence genetic risk are modifiable. In this respect, this information could help design preventive strategies and therapeutic interventions on the population at risk. In addition, these studies will strengthen the science base for risk assessment. The results will help develop a framework by which such data can be used in risk assessment to improve occupational/environmental health and disease prevention by identifying those that are most (or least) at risk of developing disease. Such framework would provide an opportunity to obtain more accurate quantitative information on the inter-individual variability likely to occur in the exposed population and could be used to establish more appropriate Permissible Exposure Limits or exposure conditions to protect individuals who are at high risk. Finally, dissecting the genetic architecture of common occupational and environmental disorders provides valuable information to further investigate gene function and its role in disease pathogenesis. This information can be used to design more appropriate in vitro and animal models for improved toxicity and risk assessment.